1. The Field of the Invention
This invention relates to steroidal hormones and, more particularly, to novel systems and methods for synthesizing natural base steroidal hormones and more especially estrogens and progesterone and estrogen-like and progesterone-like compounds and their derivatives derived as phytohormones from herbaceous plants.
2. The Background Art
Hormones are glandular chemical secretions generally formed by an organ or part of the body and carried in the bloodstream to another organ or part of the body to stimulate or retard a specific physiological activity or process. Steroidal hormones are a distinctive type of hormone which encompasses a large group of chemical compounds that are widely distributed throughout the body and involved in many important structural and functional physiological roles.
A principle component of steroidal hormones is its molecular configuration which incorporates a cyclopentanoperhydrophenanthrene ring system, commonly referred to as the "steroid nucleus." The steroid nucleus is generally characterized as consisting of three fused cyclohexane rings and a terminal cyclopentane ring of carbon atoms formed in a nonlinear or phenanthrene arrangement which provides the structural basis for many important compounds such as estrogens, progesterone, and androgens.
Estrogens include any of various natural or synthetic substances possessing the biological activity of estrus-producing hormones. Typically formed in the ovary, placenta, testis, adrenal cortex and by some plants, estrogens are generally responsible for stimulating the development and maintenance of the female secondary sex characteristics.
In general structure, estrogen consists of a group of three estrogenic hormones--estradiol (C.sub.18 H.sub.24 O.sub.2), estrone (C.sub.18 H.sub.22 O.sub.2), and estriol (C.sub.18 H.sub.24 O.sub.3)--which are synthesized mainly in the liver from cholesterol and typically transported in the circulatory system both in free and conjugated forms (approximately 50% or more are bound to plasma proteins). In function, estrogens enter target cells and bind to receptors where they influence protein synthesis and promote enzyme activation. Because estrogen is weakly anabolic, its primary anabolic targets are the secondary sex organs. However, estrogens also promote protein synthesis in other body tissues, and some tissue wasting (particularly of skeletal tissue) occurs in the absence of estrogen, as demonstrated by the rapid acceleration of osteoporosis in postmenopausal women.
Under the influence of estrogenic hormones, estrogen has been found to decrease platelet adhesiveness, increase serum levels of vitamin K-dependent clotting factors, depress the release of gonadotropins (follicle-stimulating hormone and luteinizing hormone) secreted by the anterior pituitary which influence female reproductive cycles, and suppress lactation in postpartum women. Other significant metabolic effects of estrogenic hormones include, for example: (1) depression of bone resorption, conservation of calcium and phosphorus, epiphyseal closure and enhancement of bone formation; (2) modification of carbohydrate absorption and metabolism by reducing intestinal motility (and thus the rate of sugar absorption) and by antagonizing the hypoglycemic activity of insulin; (3) alteration of liver metabolism, which results in higher plasma levels of thyroxin and cortisol binding proteins; and (4) enhancement of (.alpha.)-lipoprotein and triglyceride plasma levels and depression of (.beta.)-lipoprotein and cholesterol plasma levels.
Progesterone is another important steroidal hormone which is generally responsible for facilitating a significant physiological role in the luteal phase of the menstrual cycle and in the maintenance of a pregnancy. Formed in the corpus luteum, adrenals, testes, and placenta during pregnancy, progesterone (C.sub.21 H.sub.30 O.sub.2) typically regulates the periodicity of the sexual cycle, facilitates changes in the endometrium, adapting it for the reception of the fertilized ovum, stimulates the mammary glands, inhibits uterine musculature, and relaxes the pelvic ligaments.
Like estrogen, progesterone enters target cells and binds to receptors to influence protein synthesis. One of the predominant physiologic effects of progesterone in nonpregnant women is to promote changes in the estrogen-primed endometrium in order to convert the endometrium into a secretory mucosa. Progesterone further inhibits spontaneous uterine contractions, and at high doses can restrict the release of hypothalamic gonadotropin-releasing hormones. Moreover, high doses of progesterone generally suppress endometrial bleeding, whereas the withdrawal of progesterone typically induces endometrial sloughing and has been found to have antineoplastic activity against some cancers. While both estrogen and progesterone are necessary to produce the normal endometrial cycle, progesterone's metabolic effects are generally fewer than those of estrogen.
Based on the foregoing, physiologists agree that steroidal hormones play a major role in producing the cyclic changes characteristic in women, in addition to facilitating several other important physiological activities and processes in the body. Consequently, a hormone imbalance of estrogen and/or progesterone can have serious physiological consequences.
Therapeutic uses of steroidal hormone replacement therapy (with natural or synthetic preparations) have been developed by those skilled in the art and are being used clinically as means for increasing or supplementing the hormone balance of biological organisms, as well as for treating a wide variety of other clinical conditions. For example, the normal female reproductive system generally depends on the proper sequential balance of ovarian hormones and is, thereby, acutely susceptible to hormonal interference or imbalance. In this regard, ovarian hormones (or their synthetic analogs) have been used as a form of hormonal replacement therapy to treat various types of gynecologic and physiologic problems.
For example, as a woman ages, the functional life of the ovaries generally declines. During menopause, estrogen secretion typically declines slowly and continues for several years after menses has ended. This decline in estrogen may cause symptoms such as hot flashes and inappropriate sweating (vasomotor symptoms), palpitations, and atrophic vaginitis. Headaches, dizziness, fainting, paresthesia, and muscle and joint aches, as well as feelings of anxiety or emotional lability, may also occur. More importantly, osteoporosis commonly develops in post menopause women and is generally associated with estrogen deficiency.
The National Institute of Health Consensus Development Conference on Osteoporosis concluded that estrogen replacement therapy is one of the most effective single modalities in the prevention of osteoporosis. Consistent therewith, estrogen replacement therapy has been found to be arguably more effective at preventing osteoporosis than reversing it, and should be typically started early after menopause.
Important indications for estrogen-only hormone preparations typically relate to three major use categories: (1) replacement therapy in girls with primary hypogonadism, and relief of vasomotor symptoms in menopausal women; (2) to moderate the intensity of treatment of advanced breast or prostate cancer; and (3) treatment of estrogen deficiency relative to induced osteoporosis. Similarly, important indications for progesterone-only hormonal preparations typically relate to: (1) the treatment of functional uterine bleeding and some types of amenorrhea; (2) adjunctive and palliative therapy for metastatic endometrial or renal carcinoma and endometriosis; and (3) the investigational use of progesterone replacement therapy as a long-acting contraceptive in females.
Estrogens are commonly used in combination with progesterone to provide a broad application of use as oral contraceptive agents. Similarly, progesterone may be used to supplement estrogen replacement therapy to reduce the risk of endometrial hyperstimulation.
Preparations of estrogenic or progesterone hormones for clinical use are broadly classified into two categories: (1) natural estrogens or progesterone, their esters and semisynthetic derivatives; and (2) synthetic nonsteroidal compounds having estrogenic or progesterone activity.
Metabolically, endogenous estrogen is metabolized and conjugated to glucuronides or sulfates by the liver. Normally, a small amount of estrogen is secreted into the bile, reabsorbed by intestinal cells, and recirculated back to the liver. However, the bulk of estrogen metabolites are eliminated in the urine. In this regard, urine from pregnant mares is typically a major source of "natural" estrogen synthesized for commercial use. Moreover, since .beta.-estradiol (C.sub.18 H.sub.24 O.sub.2) is considered the most potent estrogen secreted by the ovary, estradiol or its metabolites are commonly used in drug preparations of non-synthetic estrogens.
Chemically processed synthetic estrogens being produced by those skilled in the art may include, for example, ethinyl estradiol (C.sub.20 H.sub.24 O.sub.2) and mestranol (C.sub.21 H.sub.26 O.sub.2) which are typically used therapeutically as oral contraceptives. Estrogenic hormones being used for the therapeutic treatment of cancer may include, for example, diethylstilbestrol (C.sub.18 H.sub.20 O.sub.2) and ethinyl estradiol. Diethylstilbestrol and ethinyl estradiol, however, may cause nausea and occasional vomiting. Other side-effects may involve the retention of sodium which may lead to hypertension and congestive heart failure. Accordingly, the blood pressure and cardiac status should be monitored periodically, especially when renal or cardiac disease is present. Other potential side effects are feminization and gynecomastia in males, and vaginal bleeding and breast tenderness in females.
Synthetic progesterone, such as megestrol acetate (C.sub.24 H.sub.32 O.sub.4) and medroxyprogesterone acetate (C.sub.22 H.sub.32 O.sub.3), were developed by those skilled in the art and may be used in the therapeutic treatment of advanced endometrial cancer and other hormone-dependent cancers. Chemically processed megestrol acetate and medroxyprogesterone acetate may also be used in conjunction with traditional anticancer drugs, surgery, and/or radiation therapy. Since these synthetic drugs are metabolized in the liver, they should be used cautiously in patients with liver dysfunction. In addition, progesterone therapy may cause vaginal bleeding, mild fluid retention, and hypercalcemia in patients with bone metastases.
Despite the wide-spread and growing use of hormonal replacement therapy of the type described above, the advantages and effectiveness of such prior art processed chemical base steroidal hormones has been clinically questioned as a result of the multiplicity of their serious physiological side effects. For example, estrogen-induced side effects of estrogen replacement therapy include, for example: (1) breast tenderness, enlargement, or secretion; breakthrough bleeding, changes in menstrual flow, dysmenorrhea, or amenorrhea during and after treatment; (2) a syndrome resembling premenstrual syndrome; (3) vaginal candidiasis; (4) changes in cervical eversion and cervical secretions; (5) a cystitis-like syndrome; (6) endometrial cystic hyperplasia; and (7) uterine fibromyomata. Estrogen replacement therapy may also cause changes in the libido. Headaches (including migraines), dizziness, chorea, and seizures have also been reported along with elevated blood pressure which is typically a common factor during estrogen replacement therapy.
The usual complaints associated with progesterone replacement therapy include, for example, gastrointestinal upset, headaches, and dizziness. Prolonged administration of high doses of progesterone (either natural or synthetic preparations) typically enhances gastrointestinal disturbances and usually promotes edema, weight gain, breast congestion, and menstrual abnormalities. Other effects include, for example, thromboembolism, cholestatic jaundice, depression, breakthrough bleeding, amenorrhea, insomnia, alopecia, acne, and hirsutism.
In addition to the serious side effects of chemically processed steroidal hormones, other practical problems with the prior art chemical base steroidal hormones have also emerged. For example, the cost of producing natural or synthetic steroidal hormones, such as estrogens and progesterone, can raise the market price of the drug to the point that hormonal replacement therapy becomes an unaffordable solution.
As illustrated by the various processed chemical base natural or synthetic steroidal hormone preparations which have been produced by those skilled in the art, efforts are continuously being made in an attempt to remedy the numerous therapeutic disadvantages and physiological contraindications associated with prior art steroidal hormones being used for replacement therapy. Consistent therewith, none of the prior art disclosures suggest the present compositions or methods for producing natural base steroidal hormones such as estrogens and progesterone and estrogen-like and progesterone-like compounds and their derivatives derived as phytohormones from herbaceous plants, as herein described and claimed.